A review of proposed mechanisms for neurodegenerative disease

Abstract

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.

Keywords: TDP-43; alpha-synuclein; neurodegenerative disease; neuroimaging advances; protein aggregation; selective vulnerability hypothesis; synaptic spread hypothesis; tau.

FIGURE 1

Summation of advances in neurodegenerative disease research.

FIGURE 2

Visualization of possible synaptic spread mechanism from cell 1 to cell 2, based loosely off of original figure in Brettschneider et al. (2015).

FIGURE 3

Visualization of diversity of potential mechanisms for synaptic spread, based off of diagram in Walsh and Selkoe (2016).